Predictors for metamorphopsia in eyes undergoing macular hole surgery

Metamorphopsia is an important visual symptom of macular disease. We determined predictors for metamorphopsia investigating the relationships of macular hole (MH) diameter and retinal layer thicknesses with metamorphopsia after MH surgery. Forty-two eyes of 42 consecutive patients undergoing MH surgery were retrospectively studied. Metamorphopsia was measured with M-CHARTS. Inner nuclear layer (INL) and outer retinal layer (OR) thicknesses were measured 1000 μm away from central fovea at using Spectralis. Preoperative M-CHARTS scores correlated with MH diameters (P = 0.007–0.031) and changes of temporal OR thickness (P = 0.008–0.010). Postoperative M-CHARTS score at 3 months correlated with preoperative nasal and inferior OR thicknesses (P = 0.003 and 0.016) and with changes of superior INL at 3 and 6 months (P = 0.011 and 0.025), and score at 1 month with change of temporal OR at 6 months (P = 0.033). Postoperative improvement of M-CHARTS scores correlated with changes of temporal INL and superior OR (P = 0.026 and 0.002). Multiple regression analysis revealed that MH diameter was a significant predictor for metamorphopsia. Photoreceptor displacement and inner retinal change may generate metamorphopsia in MH undergoing surgery, however MH diameter is the most powerful predictor.

Forty-one phakic eyes were performed phacoemulsification with intraocular lens implantation simultaneously with vitrectomy. During ILM peeling, BBG was used for 28 eyes and TA for 14 eyes. MHs were closed in all the eyes after initial surgery.
The preoperative BCVA did not correlate with the vertical and horizontal M-CHARTS scores (P = 0.529 and 0.417). The BCVA was significantly correlated with the vertical M-CHARTS score at 1 month postoperatively (r = 0.340, P = 0.030), but not at the other visits.
Time course of average M-CHARTS scores. The average preoperative vertical M-CHARTS score was 0.89 ± 0.56, and improved to 0.53 ± 0.42 at 1 month, 0.51 ± 0.43 at 3 months and 0.49 ± 0.45 at 6 months (all P < 0.001). The average preoperative horizontal M-CHARTS score was 0.61 ± 0.39, which improved to 0.36 ± 0.41 at 1 month (P < 0.001), 0.33 ± 0.29 at 3 months (P < 0.001) and 0.38 ± 0.39 at 6 months postoperatively (P = 0.007).  Table 3. Preoperative M-CHARTS score did not correlate with the rate of change in INL thickness at any visits. There were significant correlations between preoperative M-CHARTS scores and the rates of change in temporal OR thicknesses at all postoperative visits. Postoperative vertical M-CHARTS score at 1 month correlated with the change of superior INL thickness at 1 month and that of temporal OR thickness at 3 and 6 months, and vertical M-CHARTS score at 3 months with that of superior INL at 3 months, indicating that both inner and outer retinal structural changes after MH closure may affect postoperative metamorphopsia.

Correlations of vertical and horizontal M-CHARTS scores with the size of macular hole.
Correlation between pre-and postoperative M-CHARTS score differences and changes in inner nuclear layer and outer retinal layer thickness. The correlations between the pre-and postoperative differences in M-CHARTS score and the rates of change in retinal thickness at 1 month postoperatively are shown in Fig. 2. The difference in horizontal M-CHARTS score correlated with the rates of change in nasal and temporal INL thickness (r = 0.309, P = 0.049 and r = 0.348, P = 0.026) and the rate of change in superior OR thickness at 1 month postoperatively (r = 0.315, P = 0.045), and the difference in vertical M-CHARTS score correlated with the rate of change in superior OR thickness at 1 month postoperatively (r = 0.460, P = 0.002).
The difference in horizontal M-CHARTS score at 6 months correlated with the rate of change in superior OR thickness at 3 months postoperatively (r = 0.315, P = 0.042), and the difference in vertical M-CHARTS at 6 months correlated with the rate of change in temporal OR thickness at 1 and 3 months postoperatively (r = 0.304, P = 0.050 and r = 0.369, P = 0.016).
Thus, the greater the postoperative change of INL and OR thickness, the greater the improvement of metamorphopsia after MH surgery.

Multivariate analysis to identify predictors of the M-CHARTS score. Multiple regression analysis
was performed to identify predictors for the M-CHARTS scores at baseline and 6 months postoperatively. The dependent factors were defined as the vertical and horizontal M-CHARTS scores at baseline and 6 months postoperatively, and the independent factors defined as age, sex, rates of change in INL and OR thickness, retinal displacement (%) and basal MH diameter. The rates of change in INL and OR thickness and retinal displacement (%) for the nasal, temporal, superior and inferior sectors were selected respectively. Because vertical and horizontal basal MH diameters were strongly correlated (r = 0.961, P < 0.001, Spearman's rank correlation coefficient test), we used horizontal basal MH diameters and vertical basal MH diameters separately in different models. As shown in Tables 4 and 5, larger MH diameter is an only significant predictive factor for the higher M-CHARTS scores at baseline and 6 months postoperatively (P value range: P = 0.007-0.049).

Discussion
Our results showed that metamorphopsia at baseline correlated with the MH diameters and changes in temporal OR thickness. Patients with greater degree of postoperative thinning of the superior INL at 3 and 6 months and temporal OR at 6 months had greater degree of postoperative metamorphopsia. Improvement of the M-CHARTS   We have previously reported that the change in INL thickness significantly correlates with retinal displacement after ILM peeling, and the temporal retinal displacement correlates with the basal MH diameter 12 . The retina moves toward the optic disc during MH closure and we found that distance of retinal displacement correlated with the change in the INL thickness, but not the changes in OR thickness 12 . Dynamic structural changes of the inner retina occur during MH closure, which appears to generate part of postoperative metamorphopsia after MH surgery.
The mechanism by which retinal deformation causes metamorphopsia has been discussed in previous publications. Asymmetric elongation of the foveal tissue was associated with postoperative metamorphopsia in eyes undergoing MH surgery 8 . Park et al. 9 reported that a large extent of ILM detachment caused the square grid on the retina to move towards the optic nerve and postoperative metamorphopsia corelated with parafoveal deformation. The authors considered that metamorphopsia after MH surgery was caused by irregularities and eccentric displacement of the photoreceptor layer 15,16 . Sugiura et al. 6 reported that the area of the intraretinal cyst was most associated with metamorphopsia. It is interesting that their study did not show a positive association  Table 4. Multivariate regression analysis for M-CHARTS score at baseline. Independent factors: age, sex, INL%, OR%, RD%, MH diameter. The INL%, OR% and RD% for the nasal, temporal, superior and inferior sectors were selected respectively. Horizontal MH diameter was selected for the nasal and temporal sectors and vertical MH diameter was selected for the superior and inferior sectors. INL% and OR% were defined as the rates of change before and after surgery in INL and OR thicknesses measured in four sections of the macula: nasal, temporal, superior, and inferior, at 1000 μm away from the center of the fovea. SE standard error, CI confidence Interval, MH macular hole, INL% the rate of change in inner nuclear layer thickness, OR% the rate of change in outer retinal layer thickness, RD % the rate of change in retinal distance.  17 . Experimental studies showed that Müller cell is an optic fiber which transfers photons to photoreceptors 18,19 , and we considered that dislocated Müller cells transfer photons to the photoreceptors which located away from original positions, which creates a sensation of metamorphopsia 17 . After MH surgery, changes in INL thickness correlated with changes in metamorphopsia, suggesting that Müller cells play a role for sensation of metamorphopsia in eyes undergoing MH surgery. A shrinkage of the INL caused by retinal movement in eyes with larger MH appears to create greater postoperative scores of M-CHARTS. However, before MH surgery, MH diameter is an important parameter to determine the degree of metamorphopsia. The preoperative INL and OR thicknesses were influenced by the size of the MH, of which the baseline OR thickness correlated the pre-and postoperative metamorphopsia. Multiple regression analysis showed that the MH diameter is a predictor for the postoperative M-CHARTS score, which indicates that morphological changes in the photoreceptor layer associated with MH has great influence on postoperative metamorphopsia. In contrast, the M-CHARTS score did not correlate with retinal displacement, indicating that the displacement of retina existing relatively far away from the central fovea did not affect metamorphopsia. This means that the displacement of photoreceptor cells near the central fovea during MH closure appears to play the most important role in postoperative metamorphopsia.
The mechanism of metamorphopsia in patients with MH is explained using OCT images and schematic diagrams in Fig. 3. The photoreceptor cells near the center of the macular with the whole retinal layer are efferently displaced during the formation of the MH, detached from the retinal pigment epithelial cells, and elevated toward the vitreous. As a result, the density of photoreceptor cells increases along the optical axis and the overlapping photoreceptor cells are simultaneously stimulated with incoming light, causing metamorphopsia in which percepted images pinch toward the center. Early after MH closure, photoreceptor cells are slightly displaced from their original location, and the sensation of metamorphopsia improves as photoreceptor cells gradually return to their original positions with time.
In contrast, contraction of the ERM causes centripetal displacement of the retinal surface, distorting the alignment of photoreceptor cells and causing metamorphopsia 20 . In both the MH and the ERM, distorted Müller cells may also contribute to the development of metamorphopsia as optic guides which transfer photons to the displaced photoreceptors as proposed in our previous publications 14,17 .
The present study had several limitations. First, it was a retrospective study with a relatively small number of cases and a short follow-up period. Second, the area of ILM removal was not measured quantitatively. Third, all the retinal thicknesses were measured manually using OCT images. Because of the retinal displacement after MH surgery, the measurement points for each retinal thickness were not identical throughout observation periods.
In conclusion, basal MH diameter is a significant predictor for metamorphopsia before and after surgery. Displaced photoreceptors appear to contribute most to generate pre-and postoperative metamorphopsia. The change of INL thickness after MH surgery also correlates with postoperative metamorphopsia, which suggests that thinning of inner retinal layer simultaneously play some role for creating a sensation of metamorphopsia.

Data availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable requests.